ALLELIC LOSSES AND DNA METHYLATION AT DNA MISMATCH REPAIR LOCI IN SPORADIC COLORECTAL-CANCER

Normal and tumor DNA samples of 35 patients with sporadic colorectal c arcinoma were analyzed for microsatellite alterations at 12 markers li nked to mismatch repair loci: hMLH1, hMSH2, hMSH3, hMSH6, hPMS1 and hP MS2. Remarkably, no correlation was observed between the replication e rror phenotype (RER+) and allelic losses at these loci. Hemizygous del etions, seen in 6/35 (17%) informative cases at hMLH1, 4/27 (15 %) at hMSH2/hMSH6 and 6/34 (18%) at hMSH3, were rarely found in RER+ tumors. Since mismatch repair protein components act in molecular complexes o f defined stoichiometry we propose that hemizygous deletion of the cor responding loci may be involved in colorectal tumorigenesis through de fects in cellular functions other than replication error correction. T he analysis of the methylation status of the promoter region of hMLH(1 ) revealed that methylation might be an important mechanism of this lo cus inactivation in RER+ sporadic colorectal cancer.